Structural Properties of Target Binding by Profilaggrin A and B Domains and Other S100 Fused-type Calcium-binding Proteins

Overview

Journal J Dermatol Sci

Publisher Elsevier

Specialty Dermatology

Date 2020 Sep 7

PMID 32893105

Citations 2

Authors

Alexander J Hinbest

Sa Rang Kim

Sherif A Eldirany

Ivan B Lomakin

Joseph Watson

Minh Ho

Christopher G Bunick

Affiliations

Soon will be listed here.

Abstract

Background: Profilaggrin belongs to the S100 fused-type protein family expressed in keratinocytes and is important for skin barrier integrity. Its N-terminus contains an S100 ("A") domain and a unique "B" domain with a nuclear localization sequence.

Objective: To determine whether profilaggrin B domain cooperates with the S100 domain to bind macromolecules. To characterize the biochemical and structural properties of the profilaggrin N-terminal "AB" domain and compare it to other S100 fused-type proteins.

Methods: We used biochemical (protease protection, light scattering, fluorescence spectroscopy, pull-down assays) and computational techniques (sequence analysis, molecular modeling with crystallographic structures) to examine human profilaggrin and S100 fused-type proteins.

Results: Comparing profilaggrin S100 crystal structure with models of the other S100 fused-type proteins demonstrated each has a unique chemical composition of solvent accessible surface around the hydrophobic binding pocket. S100 fused-type proteins exhibit higher pocket hydrophobicity than soluble S100 proteins. The inter-EF-hand linker in S100 fused-type proteins contains conserved hydrophobic residues involved in binding substrates. Profilaggrin B domain cooperates with the S100 domain to bind annexin II and keratin intermediate filaments in a calcium-dependent manner using exposed cationic surface. Using molecular modeling we demonstrate profilaggrin B domain likely interacts with annexin II domains I and II. Steric clash analysis shows annexin II N-terminal peptide is favored to bind profilaggrin among S100 fused-type proteins.

Conclusion: The N-terminal S100 and B domains of profilaggrin cooperate to bind substrate molecules in granular layer keratinocytes to provide epidermal barrier functions.

Citing Articles

Cracking the Skin Barrier: Liquid-Liquid Phase Separation Shines under the Skin.

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Recent insight into intermediate filament structure.

Eldirany S, Lomakin I, Ho M, Bunick C Curr Opin Cell Biol. 2020; 68:132-143.

PMID: 33190098 PMC: 7925366. DOI: 10.1016/j.ceb.2020.10.001.

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